623

ORIGINAL ARTICLE

Fraser syndrome and cryptophthalmos: review of the

diagnostic criteria and evidence for phenotypic modules
in complex malformation syndromes
A M Slavotinek, C J Tifft
.............................................................................................................................

J Med Genet 2002;39:623–633

Fraser syndrome is characterised by cryptophthalmos, cutaneous syndactyly, malformations of the lar-

See end of article for
authors’ affiliation
.......................
Correspondence to:
Dr A M Slavotinek,
National Human Genome
Research Institute, National
Institutes of Health, Bldg
49, Room 4B75,
49 Convent Drive,
Bethesda, MD
20892-4472, USA;
aslavoti@nhgri.nih.gov
Revised version received
27 February 2002
Accepted for publication
8 April 2002
.......................
ynx and genitourinary tract, craniofacial dysmorphism, orofacial clefting, mental retardation, and
musculoskeletal anomalies. The inheritance is autosomal recessive. No diagnostic cytogenetic abnor-
malities have been documented in affected patients, and no molecular genetic studies have been
reported. We have reviewed 117 cases diagnosed as Fraser syndrome or cryptophthalmos published
since the comprehensive review of Thomas et al in 1986 in order to validate the published diagnostic
criteria and to delineate the phenotype associated with this syndrome.
Our series showed more females (57/117) than males and consanguinity was present in 29/119
(24.8%). Eighty-eight patients satisfied the diagnostic criteria for Fraser syndrome (75%).
Cryptophthalmos was present in 103/117 (88%), syndactyly in 72/117 (61.5%), and ambiguous
genitalia in 20/117 (17.1%). Ear malformations were recorded in 69/117 (59%), and renal agenesis
in 53/117 (45.3%). Use of the published diagnostic criteria excluded several patients with cryptoph-
thalmos and one or more physical feature(s) consistent with Fraser syndrome. The frequency of addi-
tional anomalies in our series was also higher than previously reported (for example, imperforate anus
or anal stenosis were found in 34/117 (29%) compared with 2/124 (2%) in the series of Thomas et
al (1986) and choanal stenosis or atresia was present in 7/117 (6%) compared to 0/124. These find-
ings emphasise the clinical variability associated with Fraser syndrome and support genetic heterogen-
eity of the syndrome. We also noted patterns of anomalies (for example, bicornuate uterus with
imperforate anus or anal stenosis and renal malformations) that are found in other syndromes and
associations without cryptophthalmos, suggesting that common modifier genes may explain some of
the phenotypic variation in Fraser syndrome.

Thomas et al.2 We have not included the seven cases reported

C
ryptophthalmos (CO) was first noted by Pliny the Elder
who described a family of three children born with a by them, but have included several patients reported in 1985
membrane over the eye. In more modern times, the first or 1986 not mentioned in the same paper. Our aim was to
report of CO with additional malformations was attributed to characterise further the phenotype associated with FS and CO.
Zehender (1872). These authors reported a female infant who
had “classical” manifestations of Fraser syndrome including
CO, syndactyly, abnormal genitalia, hypertelorism, a broad, MATERIALS AND METHODS
depressed nasal bridge, a tongue of hair extending from the Eighty-eight cases of FS satisfying the published diagnostic cri-
temple to the brow, umbilical hernia, anal stenosis, and teria were ascertained using the search terms “Fraser syn-
diastasis of the symphysis pubis. Fraser syndrome (FS) was drome” or “cryptophthalmos” on the OMIM database
recognised as a clinical entity and named after George Fraser, (www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=OMIM) and
who described two sibships with physical findings of CO, syn- PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi).3–5 7–54
dactyly, genital anomalies, laryngeal stenosis, ear malforma-
tions, and renal abnormalities.1
There are more than 200 published case reports of patients
with CO and FS and several comprehensive reviews have previ- Table 1 Diagnostic criteria for Fraser syndrome
ously been published.2–5 Diagnostic criteria for distinguishing Major criteria
between isolated CO or CO with other malformations and FS
Cryptophthalmos
were provided by Thomas et al2 following a study of 124 cases of
Syndactyly
CO (table 1). Two major criteria and one minor criterion or one Abnormal genitalia
major and at least four minor criteria were required for the Sib with Fraser syndrome
diagnosis of Fraser syndrome.2 The inheritance pattern is auto- Minor criteria
somal recessive on the basis of parental consanguinity Congenital malformation of nose
Congenital malformation of ears
(estimated to be as high as 15%)2 and multiple affected sibs
Congenital malformation of larynx
born to the same parents. There have been no reports of Cleft lip +/− palate
diagnostic cytogenetic aberrations or biochemical markers and Skeletal defects
no molecular genetic studies have been published for CO or FS. Umbilical hernia
Since the detailed review of Thomas et al,2 no large study has Renal agenesis
re-examined phenotypic findings in FS or the utility of the Mental retardation
published diagnostic criteria. We have ascertained 117 cases of
CO and Fraser syndrome published since the review of

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624 Slavotinek, Tifft

Table 2 Complications during pregnancy

Complication Frequency Reference

Oligohydramnios or anhydramnios 20 (17.1%) 4, 17, 16, 19, 21 (two cases), 29, 31, 32, 36 (three
cases), 40, 41, 44 (two cases), 47, 50 (two cases), 53
Antepartum haemorrhage 3 (2.6%) 3, 4, 51
Vaginal bleeding 3 (2.6%) 14, 42, 53
Fetal hydrops/nuchal oedema 9 (7.7%) 4 (two cases), 19, 31, 36 (two cases), 41, 44 (two cases)
Fetal ascites 9 (7.7%) 4, 29, 32, 31, 36, 44 (two cases), 47, 53
Intrauterine growth retardation 3 (2.6%) 4, 26, 40
Hypoplasia/single umbilical artery 5 (4.3%) 3, 16, 19, 26
Malnutrition in pregnancy 58
High AFP 4
Polyhydramnios 16, 26
Fetal bradycardia 3, 26
Cystic adenomatoid malformation 47

Table 3 Type of CO
Type of CO* Frequency Reference

Unilateral CO 32 (27.4%) 3 (two cases), 4 (four cases), 5, 8, 14, 17, 19, 21, 23, 28 (two cases), 31,
35, 37, 39 (two cases), 41, 44, 52, 60, 61, 62 (four cases), 65, 66 (two
cases)
Bilateral CO 62 (53%) 3, 4 (six cases), 7, 10, 11 (two cases), 12, 13, 15 (two cases), 16 (two
cases), 18, 19 (three cases), 20–22, 24, 25, 26 (two cases), 27, 28 (two
cases), 30, 32, 36 (three cases), 38, 39 (two cases), 40, 42–44, 47, 48, 49,
50, 51, 52 (two cases), 56, 57, 58 (three cases), 59, 60, 63, 64, 67–69
Absent 14 (12%) 4, 9, 16, 33, 34, 41, 45 (three cases), 50, 53, 55, 62 (two cases)
Unstated 9 (7.7%) 16, 29, 32, 45 (four cases), 46, 54

Twenty-nine cases of CO or eyelid colobomas did not satisfy
the diagnostic criteria for FS and were obtained using the
same methods.39 52 55–69 We did not include the cases reported in
Philip et al70 and King et al71 as insufficient clinical details were
provided. We also noted that the details of the four cases
reported by Vanlieferinghen et al72 were the same as described
in Francannet et al19 and we have only included these cases
once as Francannet et al.19 The patients reported by Pe’er and
BenEzra73 and Pe’er et al11 are also the same and the clinical
details in the latter paper were used. Similarly, the patient
reported by Chattopadhyay et al74 appears to be the same as the
patient in Jagtap et al37 and has been included once as Jagtap
et al.37 We included the cases of Feldman et al,55 Ohtsuka et al,56
and Wiznitzer et al7 as these cases were published in close
chronology to and omitted from the review of Thomas et al.2
For each case, the following information was collated when
available: parental ages, consanguinity, family history, sex of
proband, karyotype, and details of pregnancy including length
of gestation, weight, and other measurements at the time of
birth. We recorded eye malformations, airway malformations,
digital abnormalities, renal malformations, genital abnormali-
ties, cardiac malformations, gastrointestinal malformations,
cerebral malformations, orofacial clefting, skeletal defects,
abnormalities of the thymus, developmental status, and other
phenotypic findings.
RESULTS
Data from the 117 cases are shown in tables 2-18. There were
57 females (48.7%), 54 males (46.2%), and six (5.1%) in whom
the sex was not able to be determined. Eighty-eight patients
(75.2%) satisfied the published diagnostic criteria for FS,
whereas 29/117 (24.8%) did not (see Materials and methods
for listing of individual cases). Consanguinity was present in
29 cases (24.8%, data not shown) and the most common con-
sanguineous union was first cousins.7 11 13 19 25 29 42 50 55 Of those
born to non-consanguineous parents, one child was from
gypsy parents33 and one child was born to parents from the
same village.9 Forty-eight patients (41%) had a significant
family history of a relative with CO or physical findings
suggestive of FS (data not shown). The oldest subjects were
alive in the fourth decade of life.58
The average paternal age (rounded to the nearest whole
year) was 27 years of age and the average maternal age
(rounded to the nearest whole year) was 24 years of age (data
not shown). Thirty-six patients were reported to have a
normal female karyotype and 21 patients had a normal male
karyotype (data not shown). Two patients had an inversion of
chromosome 9 that was considered to be unrelated to
their physical findings ((46,XX,inv(9)(p11q21) and
46,XY,inv(9)(p11q21)).21
Pregnancy
Oligohydramnios was the most frequent complication during
pregnancy (17.1%, table 2). The majority of babies in whom
gestational age was stated were born at term (data not shown).
CO and ocular malformations
CO was present in 103/117 (88%) of cases and was bilateral in
62 cases (53%) and unilateral in 32 cases (27.4%, table 3). The
type of CO was often not provided but complete CO appeared
to be the most common form (data not shown). CO was com-
monly associated with a tongue of hair extending across the
lateral face (40/117, 34.2%, table 4), absent eyebrows or
eyelashes (34/117, 29.1%), and coloboma of the eyelid (21/117,
17.9%). Other abnormalities included microphthalmia (25/
117, 21.4%), anophthalmia (7/117, 6.0%), and corneal opacifi-
cation (12/117, 10.3%).
Digital anomalies
Syndactyly was the most common digital abnormality
(72/117, 61.5%, table 5). Syndactyly of the hands and feet was
present in half of the cases with syndactyly. Brachydactyly,
nail hypoplasia, and abnormal palmar creases were present in
less than 10% of patients.

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Fraser syndrome and cryptophthalmos 625

Table 4 CO and other ocular malformations

CO/ocular malformation Frequency Reference

Tongue of hair 40 (34.2%) 3 (two cases), 8, 9, 11 (two cases), 16 (two cases) 19–22, 32, 33, 37,
38, 42, 51, 52 (three cases), 56–58 (three cases), 60–62 (six cases), 63,
66 (two cases), 67–69
Absent eyelashes/eyebrows or alopecia of eyebrows 34 (29.1%) 3, 4, 10, 11 (two cases), 14, 18–20, 16 (two cases), 21, 25, 32, 37,
39, 42, 45, 48, 49, 60, 51, 52 (two cases), 58 (three cases), 61, 63, 66
(two cases), 67–69
Coloboma of eyelid 21 (17.9%) 3, 14, 21, 23, 27, 30, 42, 43, 49, 52 (two cases), 56, 58, 60, 62 (four
cases), 64, 66, 68
Groove in frontal bone/furrow to forehead/temporal 10 (8.5%) 3, 8, 16, 19, 27, 59, 60, 63, 64, 68
depression
Microphthalmia 25 (21.4%) 55–58, 3, 12, 4 (three cases), 17–19 (two cases), 20, 21, 63, 36 (two
cases), 41–43, 66 (two cases), 52, 69
Anophthalmia 7 (6.0%) 3, 4, 34, 45 (three cases), 62
Corneal opacification/corneal clouding/sclerocornea 12 (10.3%) 4, 16, 27, 33, 37, 43, 49, 58, 60, 62, 64, 67
Microcornea/absence of the cornea/corneal epithelial defect 3 (2.6%) 16, 41, 58
Abnormal anterior chamber/absence of the anterior structures 6 (5.1%) 11 (two cases), 18, 41, 52, 67, 69
Hypoplasia of the optic nerve/atrophy of optic nerve 6 (5.1%) 4 (two cases), 11, 24, 25, 52
Symblepharon/oculopalpebral synechiae 17 (14.5%) 4, 5, 8, 16, 30, 37, 39, 43, 47, 49, 60 (two cases), 61, 62, 64, 65, 68
Orbital or corneal dermoid 5, 27
Skin tag over left eye 37
Coloboma unstated 38
Ocular coloboma 5, 21, 41
Cataracts 41

Table 5 Syndactyly and other digital malformations

Digital abnormality Frequency Reference

Syndactyly - hands and feet (includes all limbs) 37 (31.6%) 4 (six cases), 7, 9, 11 (two cases), 12, 15 (two cases),
16 (three cases), 17–19 (four cases), 21, 22, 24, 29,
35–37, 41, 42, 44 (two cases), 47, 51, 53, 54
Syndactyly - hands only 9 (7.7%) 4, 8, 14, 21, 33, 34, 36 (two cases), 40
Syndactyly - feet only 4 (3.4%) 4, 38, 50 (two cases)
Bilateral syndactyly 4 (3.4%) 3, 27, 31, 39
Syndactyly unstated 18 (15.4%) 4, 5, 20, 28 (two cases), 41, 43, 45 (seven cases), 46,
47, 49, 50
Brachydactyly of first digit (includes short phalanges and metacarpals) 8 (6.8%) 14, 16 (two cases), 34, 38, 40, 50, 69
Hypoplastic, dysplastic or poorly developed nails 4 (3.4%) 11, 16, 39, 51
Single or abnormal palmar creases 10 (8.5%) 4 (two cases), 14–16, 36, 41 (two cases), 50, 51
Proximal thumbs 3, 50
Polydactyly 34, 35
Clinodactyly of the fifth digits 16, 33
Camptodactyly 50
Hyperextension of digits 26

Genital malformations Orofacial clefting

Ambiguous genitalia were found in 20/117 (17.1%, table 6). In
females, clitoromegaly was the commonest genital abnormal-
ity (21/57, 36.8%). Bicornuate uterus, uterine hypoplasia,
vaginal agenesis, and synechiae or hypoplasia of the labia were
present in more than 8% of females. In males, cryptorchidism
(17/54, 31.5%), micropenis, phimosis, chordee, hypospadias,
and scrotal hypoplasia were noted.
Nasal malformations
Nasal anomalies were common with 24 having a broad nose or
nasal bridge (20.5%, table 7), 13 with a depressed or flat nasal
bridge (11.1%), and 18 with a bifid nose or a midline nasal
groove (15.4%). Coloboma of the nares or notched nares were
present in 13/117 (11.1%).
Malformations of the ears
Malformed and/or low set ears,(63/117, 53.8%, table 8),
microtia (19/117, 16.2%), and atresia or stenosis of the exter-
nal auditory meatus (21/117, 17.9%) were recorded.
Malformations of the airway and lungs
Laryngeal stenosis or atresia was reported in 36/117 (30.8%,
table 9). Choanal stenosis or atresia (7/117, 6%) and subglot-
tic stenosis (10/117, 8.5%) were also described.
Clefting of the lip, palate, uvula, or upper gum or a combina-
tion of clefts were noted in 13/117 (11.1%, table 10). A high
arched palate was found in 14/117 (12%).
Musculoskeletal anomalies
Absence or hypoplasia of the orbital or skull bones (12/117,
10.2%) and defects in skull ossification (8/117, 6.8%) were
among the most frequent musculoskeletal anomalies (table
11). Talipes (10/117, 8.5%) and abnormalities involving the
pubic symphysis (9/117, 7.7%) were relatively common.
Gastrointestinal malformations
The commonest malformation was imperforate anus (15/117,
12.8%, table 12), but anal atresia and anal stenosis were men-
tioned in 9/117 (7.7%) and 8/117 (6.8%) cases, respectively.
Thirteen patients had a low set umbilicus (11.1%).
Renal malformations
Bilateral renal agenesis with or without agenesis of the ureters
was present in 27 of patients (23.1%, table 13) and unilateral
renal agenesis with or without ureteral agenesis in 26 cases
(22.2%). The bladder was small or absent in 20 (17.1%) and
cystic dysplasia of the kidneys was reported in 14 patients
(12%).

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626 Slavotinek, Tifft

Table 6 Malformations of female and male genitalia

Genitourinary malformation Frequency Reference

Ambiguous genitalia 20 (17.1%) 4 (two cases), 19 (two cases), 21, 24, 28, 32 (two cases),
33, 36, 39, 45 (five cases), 51, 53, 55
Female abnormalities
Clitoromegaly/prominent clitoris 21 (36.8%) 4 (two cases), 9, 10, 11, 14, 16 (two cases), 18, 24, 28,
38, 41 (two cases), 45 (three cases), 49–51, 54
Bicornuate uterus 5 (8.8%) 4 (two cases), 16, 36, 50
Absent, small, or hypoplastic uterus 5 (8.8%) 16, 34, 42, 45, 53
Vaginal agenesis, atresia, aplasia and imperforate vagina 7 (12.3%) 9, 16, 24, 32, 36, 37, 41
Synechiae, adhesions or fusion of the labia 5 (8.8%) 4 (two cases), 11, 32, 45
Hypoplasia or absence of the labia (majora or minora) 5 (8.8%) 9, 14, 19, 49, 51
Rectovaginal fistula or perineal fistula 5 (8.8%) 9, 20, 16 (two cases), 28
Persistent cloaca 2 (3.5%) 24, 45
Male abnormalities
Cryptorchidism, unilateral or bilateral 17 (31.5%) 3 (two cases), 4 (two cases), 11, 16, 17, 21, 22, 26, 28,
32, 36, 43, 44 (two cases), 45
Micropenis 8 (14.8%) 3, 4 (three cases), 21, 30, 44 (two cases)
Phimosis 4 (3.4%) 11, 21, 36, 45
Chordee 3 (5.5%) 30, 44
Hypospadias 5 (9.3%) 4 (two cases), 22, 27, 43
Hypoplastic scrotum and or atypical scrotal raphe 5 (9.3%) 16, 22, 25, 44 (two cases)
Unspecified abnormalities 2 (1.7%) 20, 37
Streak gonads/absent internal organs 4 (two cases)
Malformed Fallopian tubes 4
Hypoplastic ovaries/ovarian cyst 16, 26, 45
Large or hypertrophic labia majora 40
Hypoplastic external genitalia 16 (two cases)
Small, hypoplastic clitoris 36, 37
180 degree malrotation of penis 23
Macropenis 16
Left ovarian gonadoblastoma in situ 57

Table 7 Nasal malformations

Nasal malformation Frequency References

Broad nose and/or nasal bridge 24 (20.5%) 11, 16 (two cases), 23, 28 (two cases), 30, 32 (two cases), 37–39, 44,
49, 50 (two cases), 51, 52 (three cases), 54, 59, 68, 69
Depressed or flat nasal bridge 13 (11.1%) 10, 22, 30, 38, 39, 44, 50, 52 (three cases), 54, 55, 68, 69
Bifid nose, midline groove, or dimple to nasal tip 18 (15.4%) 8, 9, 13, 16, 19, 25, 30, 33, 37, 42, 43, 51, 52 (three cases), 62 (two
cases), 68
Coloboma of nares/notched nares 13 (11.1%) 3, 8, 9, 11, 15, 16, 22, 23, 27, 28, 42, 51, 52
Small, short, and/or flat nose 16 (13.7%) 4 (five cases), 10, 11, 19 (three case), 16 (three cases), 38, 50, 51
Nasal hypoplasia/small nostrils/hypoplasia of nasal 15 (12.8%) 14, 16 (two cases), 18, 28 (two cases), 32, 36, 39, 45 (five cases), 49, 52
root or bridge
Non-specific abnormalites of nasal shape* 9 (7.7%) 14 (two cases), 19, 32 (two cases), 31, 35, 44, 48
Single nostril/absence of nasal septum 3, 55
Atresia of the nose 45
Widely set or widely flared nostrils 24, 28
Deviated nasal septum, asymmetrical alae 37, 69

*Abnormal nose, hooked nose, beaked nose, gryphoid nose, splayed nose, downturned nasal tip.

Cerebral malformations Thymic abnormalities

Hydrocephalus was recorded four times3 4 31 55 and polymicro-
gyria or abnormal brain gyri were seen in three cases.4 Two
patients had encephaloceles.39 65 Other single findings were
mild cerebellar hypoplasia,16 holoprosencephaly with hy-
dromelia of the spinal cord,3 periventricular leucomalacia,12
diffuse gliosis of the brain,41 and low brain weight.26
Cardiac malformations
Cardiac malformations included hypertrophy of the left
ventricle,33 hypertrophic heart,16 a variant of Ebstein
anomaly,36 coarctation of the aorta,4 an atrial septal defect,37 an
interventricular communication,15 and a truncus arteriosus
and a ventricular septal defect.4 One patient had complex
heart disease with dysplasia of the pulmonary and aortic
valves and endocardial fibrosis.50 A patent foramen ovale and
patent ductus arteriosus were present in three cases26 40 44 and
one patient had a patent ductus arteriosus and dilated coron-
ary sinus.26 Dextrocardia3 and transposition of the great
vessels55 were also noted.
Absence or hypoplasia of the thymus3 36 and two thymuses26
were described.
Developmental delay/psychomotor retardation
Information regarding intellectual development was provided
in few cases. Developmental delay was present in five
patients25 37 49 52 61 and delayed motor development was found
in two.3 13 Speech delay was specified in one subject.14 Develop-
ment was normal in 13 cases.3 58 60 62 65–67 69 Hypotonia was
reported twice.13 25
Dysmorphological findings
There was no recognisable facial phenotype (table 14).
Twenty-five (21.4%) subjects had hypertelorism or pseudohy-
pertelorism, 11/117 (9.4%) had micrognathia, 8/117 (6.8%)
had microstomia, and 8/117 (6.8%) had a short neck.
Fetal and postnatal growth
In babies born at or after 33 weeks of gestation, the majority
had normal growth parameters (data not shown). Nine out of

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Fraser syndrome and cryptophthalmos 627

Table 8 Malformations of the ear

Ear malformation Frequency (%) References

Malformed and/or low set ears, can be with 63 (53.8%) 3 (two cases), 4 (nine cases), 7–12, 14, 15 (two cases), 17–19 (four cases), 20,
posterior rotation 16 (three cases), 21, 23, 24, 26 (two cases), 28 (two cases), 31, 32 (two cases),
33, 36 (three cases), 37, 39, 41 (two cases), 42, 44 (two cases), 46–49, 51, 52
(three cases), 56, 63, 64, 68
Fusion of the ear helix to scalp 3 (2.6%) 9, 13, 25
Microtia 19 (16.2%) 4, 9–12, 18, 25, 26 (two cases), 27, 28 (two cases), 36–38, 41, 44, 52, 64
Atresia/stenosis of the external auditory canals 21 (17.9%) 3 (two cases), 4, 8–11, 14, 16 (two cases), 21, 28 (four cases), 37, 40, 41, 44,
45, 47
Deafness/abnormal BAERs 7 (6.0%) 9, 10, 14, 28 (three cases), 37
Abnormal ossicles 13, 14
Small or absent tympanic membranes 10, 4
Anomalous ears 35
Two accessory tragi 56
Unilateral cholesteatoma 28

Table 9 Malformations of the airway and lungs

Airway malformation Frequency Reference

Choanal stenosis/atresia 7 (6.0%) 4, 13, 20, 24, 28 (two cases), 41

Laryngeal stenosis or atresia, narrow laryngeal vestibule 36 (30.8%) 3 (two cases), 4 (eight cases), 9, 11, 12, 14, 16 (three cases), 17, 19, 21,
36 (three cases), 38–41 (two cases), 44 (two cases), 45, 47–49, 53, 54
Stenosis at or below glottis (subglottic stenosis) 10 (8.5%) 4 (two cases), 8, 26, 28 (four cases), 29, 35
Hypoplastic epiglottis 2 (1.7%) 37, 47
Tracheal atresia/abnormality 3 (2.6%) 35, 43, 53
Enlarged, hypertrophic, or hyperechoic lungs 10 (8.5%) 4, 19, 21, 29, 36 (two cases), 44 (two cases), 47, 53
Hypoplasia of the lungs 13 (11.1%) 4 (five cases), 7, 11, 16 (two cases), 32, 39, 50 (two cases)
Abnormal lung lobation 5 (4.3%) 7, 21, 40, 44 (two cases)
Abnormal diaphragm/placement* 5 (4.3%) 21, 43, 44 (two cases), 53
Hoarse voice 35
Laryngeal stridor 8, 14
Unable to intubate 4, 16, 35
Absent pillar left tonsil 37
Fusion of arytenoids 3, 8, 14

*Downward/caudal displacement of the diaphragm, flat hemidiaphragm, and abnormalities of the diaphragm.

Table 10 Orofacial clefting

Dysmorphology Frequency Reference

Cleft lip 2 (1.7%) 41, 65

Cleft hard or soft palate 4 (3.4%) 4, 26 (two cases), 45
Cleft lip and palate 4 (3.4%) 4, 5, 16, 45
Bifid or bipartite uvula 2 (1.7%) 16*, 41
High arched palate 14 (12%) 3, 4, 9, 11, 14, 19, 22, 27, 37, 39, 41, 50, 56, 67
Lateral facial cleft 3 (2.6%) 5, 7, 45
Cleft of upper gum 38
Midline furrow of lower lip with sublabial groove 16
and notch at tip of tongue*

50 (18%) had a growth parameter below the 3rd centile (data
not shown). Fraser syndrome is compatible with normal post-
natal growth but both microcephaly37 and macrocephaly62 have
been recorded and one patient had a final height of 128 cm
(<3rd centile, 50th centile for age 8-9 years), whereas another
case had growth hormone deficiency.25
Survival
The age at reporting or age of death are shown in table 15. In
those who died in the first week of life, the commonest causes
of death were laryngeal stenosis/atresia or respiratory
insufficiency,4 16 26 32 obstructive uropathy or bilateral renal
agenesis, 4 7 16 21 31 34 41 or a combination of laryngeal and renal
malformations.12 40 46 Pulmonary agenesis and bilateral renal
agenesis were seen in one infant.11 Patients who were alive at
10 years of age or older had fewer major malformations (data
not shown) and only one of the 10 satisfied the diagnostic cri-
teria for Fraser syndrome. Interestingly, there was a strong
phenotypic similarity and concordance of the degree of sever-
ity of the disease in families for both severely
affected4 19 21 32 36 44 50 and mildly affected62 66 sibs. However,
intrafamilial variation was seen in the family described by
Hancheng,58 in which two sibs survived to the fourth decade of
life and one died at 2 months of age.
DISCUSSION
We have compiled the phenotypic features of 117 patients
with CO and FS (figs 1 and 2) reported since the review of
Thomas et al2 in 1986 and compared the incidences of pheno-
typic findings with previous reviews (table 16).2 3 Our aim was
to review the phenotypic manifestations associated with CO

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628 Slavotinek, Tifft

Table 11 Musculoskeletal abnormalities

Musculoskeletal abnormality Frequency Reference

Absence or hypoplasia of orbital or skull bones 12 (10.2%) 3, 5, 36, 37, 42, 45, 48, 52, 57, 61, 65, 69
Defects in skull ossification (parietal and occipital bones) 8 (6.8%) 4, 10, 11, 17, 16 (two cases), 18, 43
Wide sutures or fontanelles 5 (4.3%) 4 (three cases), 11, 16
Abnormalities of chest shape* 6 (5.1%) 4 (two cases), 16, 17, 21, 56
Abnormal symphysis pubis† 9 (7.7%) 3, 4 (three cases), 9, 16 (two cases), 24, 54
Talipes unspecified or talipes equinovarus 10 (8.5%) 4, 12, 16 (two cases), 19 (two cases), 28, 34, 50, 51
Contractures of large joints 5 (4.3%) 4, 11, 34, 50 (two cases)
Craniosynostosis 4
Parietofrontal depression 15
Abnormal thoracic spine 16
Thoracic kyphoscoliosis 16, 61
Lumbar lordosis 61
Sacral dimple 50
Deficient right clavicle 16
Hypoplastic or absent 12th ribs 16, 56
Supernumerary ribs 16
Talipes valgus 39
Talipes calcaneovalgus 11
Rockerbottom feet 4 (two cases)
Tibial bowing 4
Bowing of the limb bones 58
Bilateral genu recurvatum 39
Micromelia of all limbs 4

*Barrel shaped thorax, bell shaped thorax, narrow chest, pectus excavatum, funnel chest.
†Wide or separated symphysis pubis, diaphysis of pubic bones, small or absent pubis, cleft of pubic bones.

Table 12 Gastrointestinal malformations

GIT malformation Frequency (%) Reference

Anal atresia 9 (7.7%) 9, 13, 4 (three cases), 16 (two cases), 31, 51

Rectal atresia 2 (1.7%) 3, 24
Anal stenosis 8 (6.8%) 3, 8, 16, 28 (two cases), 62 (three cases)
Imperforate anus 15 (12.8%) 3, 4, 11, 20, 22, 25, 36 (two cases), 41, 45 (four cases), 51, 53
Anteriorly placed or displaced anus 7 (6.0%) 14, 16, 23, 45, 62 (three cases)
Umbilical hernia 7 (6.0%) 9, 11, 14, 16, 18, 33, 45
Low set umbilicus 13 (11.1%) 4, 11, 14, 16 (two cases), 20, 22, 24, 31, 45 (two cases), 47, 54
Malrotation of intestine/bowel or incomplete rotation 6 (5.1%) 4, 12, 16, 18, 20, 24
Fistula 28
Perianal fistula 9, 22
Intestinal fistula 45
Large or protuberant abdomen 36, 47
Lower abdominal wall defect 54
Deep set umbilical cord 34
Hypoplasia of the stomach 4, 34
Hiatus hernia 28
Duodenal stenosis 44
Hepatomegaly 11, 53
Abnormal lobulation of the liver 16
Non-fixation of the intestine 44 (two cases)
Mesenteric abnormalities with simple arterial pattern 4 (two cases)
Absent appendix 16, 21
Meckel diverticulum 17
Ectopic adrenal tissue 26
Ectopic pancreatic tissue 40

and FS and to examine the efficacy of the published diagnos-
tic criteria.2 The frequency of malformations in this patient
group does not differ significantly from the frequencies
reported by Gattuso et al.3 However, they are lower than those
reported by Thomas et al2 owing to selectivity of the latter
paper in including only patients in whom the presence or
absence of a feature had been documented. The incidence of
published malformations could also be skewed because of the
preferential inclusion of rare features and complications or
severely affected patients in medical publications in a well
described syndrome.
Our data show an increased incidence of consanguinity
(24.8%) compared to the incidence of 15% published by Tho-
mas et al,2 consistent with autosomal recessive inheritance.
The prevalence of FS has previously been estimated to be
approximately 11 cases in 100 000 live births.45
CO is considered to be the single most important diagnostic
malformation in FS. Complete CO is usually bilateral and can
be associated with absence or poor development of the
eyebrows, eyelashes, gland structures and conjunctival sac,
microphthalmia, symblepharon, and abnormalities of the
anterior chamber of the eye.8 75 In incomplete or atypical CO,
rudimentary lid structures with small, lateral conjunctival
sacs are present with small palpebral fissures, microphthal-
mia, and symblepharon.8 75 CO should be differentiated from
microblepharon (vertical shortening of the eyelids)76 and
mesodermal corneal metaplasia.77 78
Abortive CO or congenital symblepharon and ablepharon
are descriptive terms used to describe an upper eyelid without

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Fraser syndrome and cryptophthalmos 629

Table 13 Renal malformations

Renal malformations Frequency Reference

Unilateral renal agenesis 22 (18.8%) 3, 9, 14, 18–21, 24, 28 (three cases), 35, 38, 41, 43, 45
(four cases), 51, 52, 54
Unilateral renal agenesis with agenesis of ureter 4 (3.4%) 32 (two cases), 44, 45
Bilateral renal agenesis 6 (5.1%) 12, 15, 16, 19, 39, 44
Bilateral renal agenesis with agenesis of ureters 21 (17.9%) 4 (seven cases), 7, 11, 16 (two cases), 19, 21, 29, 31, 34,
36, 40–42, 53
Cystic dysplasia of kidneys or renal cysts 14 (12%) 4 (four cases), 9, 17, 19, 32, 36, 44–46, 50 (two cases)
Unilateral or bilateral renal hypoplasia or small kidneys 14 (12%) 3, 4 (three cases), 8, 9, 17, 27, 29, 32 (two cases), 49, 50
(two cases)
Absent, hypoplastic, or small bladder with or without urethra 20 (17%) 4 (four cases), 7, 11, 16 (two cases), 19, 21, 36 (two cases),
39, 40, 42, 44 (two cases), 45, 50, 53
Agenesis of entire urinary apparatus 29
Solitary pelvic kidney* 20, 24
Bilateral renal artery agenesis 41
Enlarged kidneys 50
Duplex left kidney system/two left ureters 3, 26
Hydronephrosis 4, 36
Renal dysplasia 45 (two cases), 49
Hypertrophied or thick bladder 4, 17
Bladder pseudexstrophy 54
Anterior urethral atresia with deformed urinary bladder, bilateral hydronephrosis, and 46
dilated ureters and umbilical discharge of urine

*Included in unilateral renal agenesis.

Table 14 Dysmorphology findings

Dysmorphology Frequency Reference

Potter facies 3 (2.6%) 19, 34, 44

Facial asymmetry 6 (5.1%) 3, 13, 15 (two cases), 36, 69
Abnormalities of skull shape* 5 (4.3%) 4, 16 (two cases), 40, 56
Sloping forehead 4 (3.4%) 17, 50 (two cases), 51
Prominent, protuberant, and/or broad forehead 5 (4.3%) 4, 14, 16 (two cases), 51
Low posterior hairline 3 (2.6%) 12, 33, 37
Hypertelorism or pseudohypertelorism 25 (21.4%) 9, 14, 16 (two cases), 18, 21, 28 (two cases), 33, 37, 38, 40, 45 (two
cases), 49, 50 (two cases), 51, 56, 62 (six cases)
Frenula or thick frenula, tongue tie, short frenula 5 (4.3%) 8, 3, 4, 28, 56
Microstomia 8 (6.8%) 16, 19 (three cases), 37, 40, 43, 51
Micrognathia 11 (9.4%) 4 (two cases), 16, 26 (two cases), 44 (two cases), 45, 50 (two cases), 51
Short neck with redundant skin and/or extra skin 8 (6.8%) 3, 7, 16 (two cases), 33, 50 (two cases), 51
Widely spaced nipples 5 (4.3%) 3, 38, 52 (two cases)
Haemangioma 4 (3.4%) 3, 8, 11, 48
Non-specific dysmorphism 27, 29
Hirsutism 19
Upward slanting palpebral fissures 37, 50
Upsweeping eyebrows 16
Epicanthic folds 45
Blepharophimosis 37, 45
Telecanthus 23, 49
Long philtrum 21, 50
Short philtrum 16, 32
Thin vermilion border to the lips, dowrnturned lips 26 (two cases)
Thick lips 69
Fibrous band of buccal mucosa 69
Relative macrostomia and macroglossia 50
Hypoplastic nipples 45
Oculocutaneous albinism 68
Vitiligo 61

*High, narrow skull, scaphocephaly, dolichocephaly, brachycephaly, flat occiput.

a well defined margin that is adherent to the cornea, often
with a small globe and keratinisation of the cornea.8
Symblepharon and ablepharon have been considered by some
authors to be an abortive form of CO8 79 and by others to con-
stitute a separate pathological entity.80 The degree of CO and
the range of ocular abnormalities in FS was very variable
(tables 3 and 4) and many patients had complete CO in one
eye with incomplete or abortive CO affecting the other eye
(data not shown).
We found patients who had symblepharon and ablepharon
and phenotypic features consistent with FS, suggesting that
symblepharon is part of the ocular manifestations of FS. The
ocular abnormalities in FS were almost all confined to the
anterior chamber of the eye with the exception of six patients
who had hypoplasia or atrophy of the optic nerve (table 4).
In our series, 14 (12%) patients did not have
CO.4 9 16 33 34 41 45 50 53 55 62 Most of these patients had other ocular
abnormalities consistent with FS (for example, corneal
clouding,4 sclerocornea,33 microphthalmia,55 anophthalmia,34 62
microcornea,41 and a lateral tongue of hair,62 and 78.6% satis-
fied the diagnostic criteria for FS (data not shown). However,
in the absence of CO, anterior chamber abnormalities could
conceivably be confused with other malformation syndromes
(for example, Walker-Warburg syndrome or Peters’ plus

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630 Slavotinek, Tifft

Table 15 Survival of affected subjects

Survival Frequency Reference

Alive up to 4 weeks 5 23, 39, 46, 52, 59

Alive up to 1 year 16 3 (two cases), 8, 11, 14, 20, 22, 23, 30, 39, 52 (two cases), 57, 63, 64, 67
1-10 years 16 5, 9, 13, 25, 28 (four cases), 33, 35, 39, 43, 48, 54, 66, 69
10-20 years 8 37, 60 (two cases), 61, 62, 65, 66, 68
Older than 20 years 2 58 (two cases)
Age unstated, alive 18 10, 18, 24, 38, 41, 45 (six cases), 49, 60, 62 (five cases)
Stillborn or spontaneous abortion 8 4 (two cases), 15, 19, 26, 42, 50, 51
Termination of pregnancy 15 4, 15–17, 19, 21, 29, 36 (two cases), 44 (two cases), 47, 50, 53, 55
Died, age uncertain 1 39
Died in first week of life 24 4 (eight cases), 7, 11, 12, 16 (two cases), 19 (two cases), 21, 26, 31, 32 (two
cases), 34, 40, 41, 46
Died in first year of life 4 3, 27, 56, 58

diagnostic criteria. Without CO, FS can be overdiagnosed

Table 16 Comparison of frequencies of phenotypic because of the relatively high frequency of digital and genital
features in CO and FS abnormalities in multiple congenital anomaly syndromes.
Ref 2 Ref 3 Our series In the patients with CO who did not satisfy the diagnostic
Physical finding (n=124) (n=63) (n=117) criteria for FS, only one had CO without any other phenotypic
CO 85% 93% 88% findings and with an unremarkable family history.60 Auto-
Unilateral 25% 24.8% somal recessive inheritance in isolated CO should still be con-
Bilateral 57% 47.9% sidered and three affected patients with CO as the sole physi-
Unstated 10% cal finding were born to consanguineous parents.39 A common
Extended hair growth 34% 34.2%
anomaly found in addition to CO without FS was a tongue of
Facial asymmetry 10% 5.1%
Ear abnormalities 84% 44% 59% hair extending from the scalp to the lateral eyebrow (table
Atresia/stenosis eam 15% 17.9% 4).58 We consider that this finding makes an underlying diag-
Nasal abnormalities 85% 37% nosis of FS with the implication of autosomal recessive inher-
Cleft lip and palate 11% 7% 11.1% itance more likely and would consider it as having at least
Renal abnormalities 37%
equal importance to a minor diagnostic feature.
Renal agenesis 84% 37% 45.3%
Bladder abn 10% 17% The incidence of syndactyly in this patient cohort was
Cystic dysplasia 3% 12% 61.5% (table 5), less than the frequency of 79% reported by
Abnormal genitalia 80% 49% Thomas et al.2 However, the syndactyly in many patients was
Indeterminate sex 6% 5.1% distinctive because of the involvement of both upper and lower
Abnormalities in females 54% limbs (table 5) and the extensive nature of the cutaneous
Clitoral hypertrophy 39% 36.8%
Bicornuate uterus 14% 8.8%
webbing, which frequently included all digits (data not
Vaginal atresia 14% 12.3% shown). A range of external and internal malformations of
Cystic ovaries 11% the genitalia were described, fully justifying the inclusion of
Rudimentary uterus 4% 8.8% these abnormalities as major diagnostic criteria.2
Abnormalities in males 41% The minor criteria of malformations of the ears and nose
Cryptorchidism 24% 31.5%
Micropenis 21% 14.8%
can be non-specific and more weighting should be given to
Hypospadias 3% 9.3% these features if they are included in the distinctive anomalies
Syndactyly 79% 54% 61.5% found in FS, such as coloboma of the nares or notched nares
Laryngeal atresia 83% 21% 30.8% (table 7). Orofacial clefting (table 10) and mental retardation
Lung hypoplasia 7% 11.1% were infrequent and these criteria were rarely helpful in
Anal stenosis/atresia 6% 16.2%
establishing the diagnosis. No mention has been made of
Talipes 6% 10.2%
Congenital heart disease 6% 12% gastrointestinal tract malformations in the diagnostic criteria
Umbilical hernia 28% 12% 6% and we would recommend consideration of malformations
Umbilicus displaced 6% 11.1% such as anal atresia, rectal atresia, anal stenosis, and imperfo-
rate anus as minor criteria owing to the occurrence of these
features in more than 25% of affected subjects (table 12). A
low set umbilicus may be more frequent and hence more
diagnostically useful than an umbilical hernia (table 12).
syndrome). The presence of microphthalmia or anophthalmia Renal agenesis has previously been considered to be an
without CO in a sporadic case constitutes a further diagnostic important diagnostic feature in FS and we would agree that
dilemma. For example, a male reported by Glanz et al81 as hav- this abnormality is pertinent to the diagnosis.82–84
ing Lenz microphthalmia because of short palpebral fissures The FS phenotype is complex and pleiotropic and therefore
could be considered to satisfy the diagnostic criteria for FS has significant overlap with other malformation syndromes.
with syndactyly, cryptorchidism and hypospadias, renal hypo- We were interested to determine if there were distinct patterns
plasia, and a cleft palate. of physical features within the FS phenotype. Recently, more
The diagnosis of FS must therefore be made with caution in complex modes of inheritance involving modifier genes or
patients who do not have CO or a family member with CO, three altered alleles have been described for a different auto-
even if other ocular abnormalities consistent with FS are somal recessive condition, Bardet-Biedl syndrome (BBS).85 86
present. For example, in the patient reported by Martinez- We therefore speculated that the more complex modes of
Frias et al33 who had sclerocornea, syndactyly, ambiguous inheritance identified in BBS could also be described for other
genitalia, a furrowed nasal tip, low set, posteriorly rotated ears, pleiotropic syndromes and that, in some cases, the phenotypic
and an umbilical hernia, the authors did not consider that the consequences of the different genes or pathways may be iden-
diagnosis of FS was correct although this patient did fulfil the tifiable within a syndromal phenotype.

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Fraser syndrome and cryptophthalmos 631

Table 17 Malformations found in addition to vaginal agenesis in FS females

Vaginal Gastrointestinal Renal Cardiac
Author malformations malformations malformations malformations Other

9 Vaginal atresia Anal atresia L renal agenesis Deafness

16 Vaginal atresia Anal stenosis R renal dystopia Bicornuate uterus
24 Vaginal atresia Rectal atresia Pelvic kidney Choanal atresia
32 Vaginal atresia Renal cysts
36 Vaginal atresia Imperforate anus Ebstein anomaly Bicornuate uterus
50 Vaginal atresia Sib with renal cysts Atrial septal defect Deafness
41 Vaginal atresia Bilateral renal agenesis Bicornuate uterus/choanal atresia

Table 18 Relative incidence of phentyopic features in FS

Incidence in
Phenotypic feature Incidence in FS patients with VA Significance

Vaginal agenesis 7/57 (12.3%) –

Anal stenosis 34/117 (29%) 4/7 (57%) p=0.14
Renal cystic dysplasia 14/117 (12%) 2/7 (28.6%) p=0.55
Cardiac malformations 14/117 (12%) 2/7 (28.6%) p=0.55
Deafness 7/117 (6%) 2/7 (28.6%) p=0.55
Choanal atresia 7/117 (6%) 2/7 (28.6%) p=0.55
Bicornuate uterus 5/57 (8.8%) 3/7 (42.9%) p=0.121

No phenotype-genotype correlation has as yet been consist-
ently described for BBS patients. However, syndactyly, imper-
forate anus, Hirschsprung disease, cardiac defects, and female
upper genitourinary tract malformations have previously been
found with increased frequency in BBS patients with
hydrometrocolpos owing to vaginal agenesis compared to
unselected BBS patients (data not shown). In this patient
cohort, we found seven females who fulfilled the diagnostic
criteria for FS and who had vaginal agenesis or vaginal atresia.
It was surprising to find that all of these patients also had at
least one other finding consistent with the above pattern such
as anal abnormalities, renal malformations including renal
agenesis or renal cysts, and bicornuate uterus (table 17). In
addition, cardiac abnormalities were identified in two
patients41 50 and one patient did not have CO.16 The finding is
more striking if one considers the relative rarity of some of
these findings in FS (table 18). This phenotypic subset has
some similarity to the MURCS association (Muellerian duct
aplasia, renal aplasia, and cervical dysplasia) and the Rokitan-
sky malformation sequence of vaginal atresia and uterine
hypoplasia or a bicornuate uterus and renal agenesis.87 88
Interestingly, corneal anaesthesia and punctate epithelial
opacities have been described in the MURCS association89 and
a child with bilateral microtia and hypoplasia of the external
ear canals, a cleft palate, hypoplastic thumbs, renal agenesis,
pulmonary agenesis, and genital hypoplasia has been consid-
ered to have physical features consistent with MURCS associ-
ation and Nager acrofacial dysostosis.90
Similarly, we found that laryngeal stenosis was present in
35/117 of patients with FS (29.9%) and stenosis of the exter-
nal auditory meatus in 21/117 of FS patients (17.9%). Both of
these malformations were present in 11 patients (52.4%,
tables 12 and 13). This association is significant with a p value
of 0.046. Although hypertelorism, hypopspadias, and laryn-
geal malformations are found in both Opitz syndrome and FS,
there did not appear to be any association of these features in
this patient group (data not shown).
Modifier genes are important determinants of phenotypic
variation and have been shown to be clinically important in
diverse conditions, including sensorineural deafness,90 cystic
fibrosis,91 hypertrophic cardiomyopathy,92 early onset
glaucoma,93 and keratin filament disorders.94 Modifier genes
can also have tissue specific effects.95 The significance of modi-
fier genes in the generation of the variability of the FS pheno-
type is unknown but is not supported by the strong familial
concordance in phenotype in many reported cases (see above).
We therefore suggest that subsets of physical anomalies or
phenotypic modules can be conserved across different
syndromes and that they may prove to be a useful means for
the delineation of specific abnormalities within a syndrome
and for the determination of relevant molecular screening
tests. The pathogenesis of phenotypic modules could include
disruption to a morphogenetic field or a developmental
field,96 mutation specific effects, or malfunction of temporally
distinct genes. Consideration of the physical findings in a syn-
drome as a series of interacting phenotypic modules may also
be a useful method for determining phenotype-genotype cor-
relations in the future.
CONCLUSION
We have reviewed 117 patients diagnosed with FS and CO
since the publication of the diagnostic criteria for FS by Tho-
mas et al.2 The diagnosis should be made with caution in
probands and families without CO, although in the presence
of typical findings, CO is not essential for the diagnosis. The
physical features of orofacial clefting, umbilical hernia, and
mental retardation were less useful in making the diagnosis,
whereas gastrointestinal tract malformations may be helpful.
We also found that patients with vaginal agenesis and FS
had a pattern of additional malformations previously de-
scribed in MURCS association and BBS. This suggests that
there is conservation of a subset of phenotypic features
between different syndromes and that unusual mechanisms
of inheritance such as modifier genes or triallelic inheritance
may be present in malformation syndromes other than BBS.
.....................
Authors’ affiliations
A M Slavotinek, National Human Genome Research Institute, National
Institutes of Health, Bldg 49, Room 4B75, 49 Convent Drive, Bethesda,
MD 20892-4472, USA
C J Tifft, Department of Medical Genetics, Children’s National Medical
Center, 111 Michigan Ave NW, Washington DC 20010, USA

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632
Figure 1 Profile of a baby with Fraser syndrome showing complete
cryptophthalmos.
Figure 2 Hands of baby with Fraser syndrome showing extensive
soft tissue syndactyly. Both photographs are reproduced with the
kind permission of Dr Samir S Amr, MD, FCAP, Pathology Services
Division, Dhahran Health Center, Saudi Aramco and the Saudi
Medical Journal (previously published as figures in reference 42,
Saudi Med J 1996;17:251–5).
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